Two skin cells of a mouse show the flow of calcium into the cell in response to a dose of histamine (lower panel). Duke researchers have shown that an ion channel called TRPV4 is the beginning of a chain of messages that ends up signaling “itch” to the brain. Credit: Yong Chen, Duke University
A potential drug target for itching sensations has been developed by researchers. Their work shows that skin cells – when exposed to certain itch-producing chemicals – can powerfully regulate nearby sensory nerve cells and facilitate transmission of the itchy feelings to the brain. The ion channel TRPV4 functions in skin cells as a pivotal switch in this newly revealed signaling pathway. Prof. Wolfgang Liedtke, M.D., Ph.D said: “We can now envision developing topical treatments for the skin that target specific molecular pathways to suppress itch and inflammation.”
In a 2013 study Liedtke and his collaborators showed that an ion channel protein abundant in skin cells called TRPV4 was crucial for conveying feelings of pain caused by over-exposure to ultraviolet-B radiation, such as in sunburn. The team found that UVB switched on TRPV4, which then caused skin cells to release a molecule called endothelin-1, implicated in both pain and itch sensations. But the scientists wondered whether TRPV4 was also involved in itch.
In the new study, Liedtke’s team used genetically engineered mice in which they dialed down TRPV4 selectively in the animals’ skin cells and then exposed them to a handful of itch-causing chemicals. Remarkably, the mice scratched much less in response to the triggers known to convey ‘histaminergic itch’, which has a range of causes, including bug bites and certain medications, that can set off the allergic response.
MOA: TRPV4 triggers a rush of calcium into the cell and the flipping “on” of a molecular switch called ERK, (extracellular-signal-regulated kinase) into its activated form, pERK. Drugs that block TRPV4 or pERK, when applied as topical ointments, quelled scratching in mice. Experiments in isolated mouse and human skin cells further corroborated the group’s findings.
TRPV4 is present on the surface of cells, which makes it an excellent target to reach with topically-applied drugs, Liedtke said. Before TRPV4 blockers could be used to treat people, however, they will need to be further formulated and then assessed in animals and human clinical trials. In contrast, pERK is present not on the surface of skin cells but within them, and targeting it for the treatment of other conditions led to unwanted side effects. Liedtke is more skeptical of this approach.
Liedtke’s neuro-dermatology team is interested in understanding the cell-to-cell communication within skin, and what sustains itch over longer time periods. Moreover, individuals naturally have varying susceptibility to itch, and it will be important to understand whether underlying TRPV4 molecular pathways are involved in such differences. “Such studies, combined with DNA sequencing, can perhaps accelerate the dawning of personalized medicine and its extension into the dermato-neurology arena,” Liedtke said.
https://today.duke.edu/2016/03/itchy
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